Indazolylcyanoethylamino compound, compositions of same, method of making, and methods of using thereof

ABSTRACT

The compound of formula I:compositions thereof, processes for their preparation, and their uses as pesticides.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of priority to U.S. ProvisionalApplication No. 62/769,850, filed Nov. 20, 2018, which is incorporatedherein by reference.

FIELD OF THE INVENTION

The present disclosure relates to an indazolylcyanoethylamino compoundof formula I or formula II, a composition comprising the compound, amethod of making the compound, a use of the compound and a methodcomprising the compound for treating and/or preventing a parasiticinfection in an animal.

Any foregoing applications and all documents cited therein or duringtheir prosecution (“application cited documents”) and all documentscited or referenced in the application cited documents, and alldocuments cited or referenced herein (“herein cited documents”), and alldocuments cited or referenced in herein cited documents, together withany manufacturer's instructions, descriptions, product specifications,and product sheets for any products mentioned herein or in any documentincorporated by reference herein, are hereby incorporated herein byreference, and may be employed in the practice of the invention.

Citation or identification of any document in this application is not anadmission that such document is available as prior art to the presentinvention.

BACKGROUND OF THE INVENTION

The control of parasites, particularly endoparasites, by means of anactive ingredient having a cyanoethylamino group has been described byvarious patents or patent applications including International PatentPublication Nos. WO 2004/024704 (U.S. Pat. No. 7,084,280), WO2005/044784, WO 2005/121075 and WO 2006/043654 as well as EP 953565(U.S. Pat. No. 6,239,077) and EP 1445251, all incorporated herein byreference.

In addition, certain indazolylcyanoethylamino compounds having abicyclic heteroaryl component are known. For example,aryloazol-2-yl-cyanoethylamino compounds are described in PCTPublication Nos. WO 2008/144275 and WO2010/056999, both incorporatedherein by reference in their entirety. However, the compound of thepresent invention has not been specifically described.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides a compound of formulaI:

and/or a pharmaceutically acceptable salt thereof and/or an enantiomerthereof.

In another embodiment, the invention provides a compound of formula II:

and/or an acceptable salt thereof and/or an enantiomer thereof.

In another embodiment, the invention provides a pesticidal orparasiticidal composition comprising a compound of formula I or acompound of formula II and a pesticidally-acceptable orparasiticidally-acceptable carrier. In some embodiments, thecompositions are suitable for oral administration to an animal. In otherembodiments, the compositions are in the form for administration byinjection. In other embodiments, the compositions are in the form fortopical administration to an animal, including pour-on or spot-onformulations.

In another embodiment, the invention provides a method for treatingand/or preventing an endoparasitic infection in a mammal which comprisesadministering an effective amount of a compound of formula I or formulaII, or pharmaceutically acceptable salts thereof, or a compositioncomprising the compound or salt, to an animal in need thereof.

In yet another embodiment, the invention provides for the use of thecompound of formula I or formula II, or pharmaceutically acceptablesalts thereof, for treating or preventing an endoparasitic infection inan animal. The invention also provides for the use of the compound offormula I or formula II, or salts thereof, in the manufacture of amedicament for the treatment or prevention of an endoparasitic infectionin an animal.

The compounds, compositions, methods and uses of the invention areeffective for treating animals including mammals, birds and fish.Examples of mammals include, but are not limited to, humans, cattle,sheep, goats, llamas, alpacas, pigs, horses, donkeys, dogs, cats andother livestock or domestic mammals. Examples of birds include turkeys,chickens, ostriches and other livestock or domestic birds. The use ofthe compounds of formula I and formula II to protect ruminant animalssuch as cattle and sheep from endoparasites is particularly useful.

In one embodiment, the methods and uses of the invention are effectiveagainst an endoparasitic infection caused by a helminth selected fromthe group consisting of Anaplocephaela (Anoplocephala), Ancylostoma,Anecator, Ascaris, Brugia, Bunostomum, Capillaria, Chabertia, Cooperia,Cyathostomum, Cylicocyclus, Cylicodontophorus, Cylicostephanus,Craterostomum, Dictyocaulus, Dipetalonema, Dipylidium, Dirofilaria,Dracunculus, Echinococcus, Enterobius, Fasciola, Filaroides, Habronema,Haemonchus, Metastrongylus, Moniezia, Necator, Nematodirus,Nippostrongylus, Oesophagostumum, Onchocerca, Ostertagia, Oxyuris,Paracaris, Schistosoma, Strongylus, Taenia, Toxocara, Strongyloides,Toxascaris, Trichinella, Trichuris, Trichostrongylus, Triodontophorous,Uncinaria, Wuchereria, and combinations thereof.

In another embodiment, the methods and uses of the invention iseffective against an endoparasitic infection caused by a helminthselected from the group consisting of Haemonchus contortus, Ostertagiacircumcincta, Trichostrongylus axei, Trichostrongylus colubriformis,Cooperia curticei and Nematodirus battus, or combinations thereof.

In another embodiment, the compounds, compositions, methods and uses ofthe invention are effective against resistant strains of theendoparasites listed in the two previous paragraphs.

In another embodiment, the invention provides a process for themanufacture of a compound of formula I or formula II.

DETAILED DESCRIPTION OF THE INVENTION

The term “about,” as used herein, means approximately, in the region of,roughly, or around. When the term “about” is used in conjunction with anumerical range, it modifies that range by extending the boundariesabove and below the numerical values set forth. In general, the term“about” is used herein to modify a numerical value above and below thestated value by a variance of 10%. In one specific embodiment, the term“about” or “approximately” means within 20%. In another embodiment, theterm “about” means within 5% of a given value or range.

Numerical ranges recited herein by endpoints include all numbers andfractions subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2,2.75, 3, 3.90, 4, and 5). It is also to be understood that all numbersand fractions thereof are presumed to be modified by the term “about.”

The term “animal” is used herein to include all mammals, birds and fishand also include all vertebrate animals, including humans. Animalsinclude, but are not limited to, humans, cats, dogs, cattle, chickens,cows, deer, goats, horses, donkeys, llamas, alpacas, pigs, sheep andyaks. Examples of birds include turkeys, chickens, ostriches and otherlivestock or domestic birds. It also includes an individual animal inall stages of development, including embryonic and fetal stages.

The term “effective amount” as used herein means a concentration of theactive agent in the composition sufficient to elicit the desiredbiological response to the target parasite(s) after administration ofthe composition to the animal, as measured by methods known in the artand/or described in the examples herein. In some embodiments, an“effective amount” of the active agent in the composition will providean efficacy of at least 70% against the target parasite compared to anuntreated control. In other embodiments, “an effective amount” of theactive agent will provide an efficacy of at least 80%, or at least 85%compared to untreated controls. More typically, “an effective amount” ofthe active agents will provide an efficacy of at least 90%, at least93%, at least 95% or at least 97% against the target parasite.

In an embodiment, the present invention includes the compound of formula(I):

and/or an acceptable salt thereof and/or an enantiomer thereof.

In another embodiment, the present invention provides a compound offormula II:

and/or an acceptable salt thereof and/or an enantiomer thereof.

In one embodiment, the compound of formula I or formula II may beenriched in an enantiomer. As defined herein, enriched in an enantiomermeans that the compound of formula I or formula II is enriched in the Ror S enantiomer relative to the other enantiomer in a ration of at least80:20 by weight. In other embodiments, the compound of formula I orformula II is enriched in an enantiomer (either R or S) in a ratio of atleast 90:10, 95:5 or 97:3 by weight. In yet another embodiment, thecompound of formula I or formula II is enriched in an enantiomer in aratio of at least 98:2 or 99:1 by weight. In an embodiment, the compoundof formula I or formula II may be the compound of formula I-R, I-S, II-Rand/or II-S, respectively, and/or an acceptable salt thereof:

The compounds of formula I and/or formula II and/or a salt and/or anenantiomer thereof are highly active against endoparasites in vitro andin vivo. In particular, it has been found that the compound of formula Iexhibits surprisingly potent activity against certain endoparasites,including Haemonchus contortus, when compared with compounds having verysimilar structures and substitution patterns. The improved activity ofthe compound of formula I is surprising and unexpected.

In an embodiment, the compound of formula (I) may be prepared by thefollowing scheme:

The compound of formula 1, commercially available 3,4-dichlorotoluene,may be halogenated, e.g., brominated, according to methods known tothose of skill in the art to produce the compound of formula 2. Thecompound of formula 3 may be prepared by metalation of the C—Br bond of2 followed by addition of a formylating agent, e.g.,N,N-dimethylformamide. The compound of formula 3 may be nitratedaccording to methods known to those of skill in the art to produce thecompound of formula 4. Difluorination of the compound of formula 4,e.g., with a fluorinating agent such as, or BAST, provides the compoundof formula 5. Reduction under conditions known to those of skill in theart provides aniline 6. Aniline 6 is then converted to heterocycle 7a bydiazotization under standard conditions known to the person of skill inthe art. Alkylation with a haloacetone, e.g., chloroacetone, to produce7b, followed by reaction with cyanide in ammonium chloride providesaminonitrile 8. Reaction of 8 with 4-trifluoromethylthiobenzoyl chlorideprovides compound I.

Another embodiment of the invention includes parasiticidal compositionswhich comprise the compound of formula I and/or formula II. Thecomposition of the disclosure can also be in a variety of forms whichinclude, but are not limited to, oral formulations, injectableformulations, and topical, dermal or subdermal formulations. Theformulations are intended to be administered to an animal which includesbut is not limited to mammals, birds and fish. Examples of mammalsinclude but are not limited to humans, cattle, sheep, goats, llamas,alpacas, pigs, horses, donkeys, dogs, cats and other livestock ordomestic mammals. Examples of birds include turkeys, chickens, ostrichesand other livestock or domestic birds. The use of the compound offormula I or II to protect companion animals such as dogs and cats fromendoparasites is particularly useful.

Veterinary compositions: The compounds of formula I and formula II andcompositions comprising the compounds are useful for the prevention andtreatment of parasitic infestations/infections in animals. Thecompositions of the invention comprise an effective amount of at leastone compound of formula I or II, or a veterinarily acceptable saltthereof, in combination with a veterinarily acceptable carrier ordiluent and optionally other non-active excipients. The compositions maybe in a variety of solid and liquid forms which are suitable for variousforms of application or administration to an animal. For example, theveterinary compositions comprising the inventive compounds may be informulations suitable for oral administration, injectableadministration, including subcutaneous and parenteral administration,and topical administration (e.g., spot-on or pour-on), dermal orsubdermal administration.

The compositions of the invention may be in a form suitable for oral use(see, e.g., U.S. Pat. No. 4,564,631, which is hereby incorporated byreference in its entirety), dietary supplements, troches, lozenges,chewables including soft chewable compositions, tablets, hard or softcapsules, bolus, emulsions, aqueous or oily suspensions, aqueous or oilysolutions, oral drench formulations, dispersible powders or granules,premixes, syrups or elixirs, enteric formulations or pastes.Compositions intended for oral use may be prepared according to anymethod known in the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more sweeteningagents, bittering agents, flavoring agents, coloring agents and/orpreserving agents in order to provide pharmaceutically elegant andpalatable preparations.

Tablets may contain the active ingredient in admixture with non-toxic,pharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for example,starch, gelatin or acacia, and lubricating agents, for example,magnesium stearate, stearic acid or talc. The tablets may be uncoated orthey may be coated by known techniques to delay disintegration andabsorption in the gastrointestinal tract and thereby provide a sustainedaction over a longer period. For example, a time delay material such asglyceryl monostearate or glyceryl distearate may be employed. They mayalso be coated by the technique described in U.S. Pat. Nos. 4,256,108;4,166,452; and 4,265,874 (all incorporated herein by reference in theirentirety) to form osmotic therapeutic tablets for controlled release.

Oral formulations include hard gelatin capsules, wherein the activeingredient is mixed with an inert solid diluent, for example, calciumcarbonate, calcium phosphate or kaolin. Capsules may also be softgelatin capsules, wherein the active ingredient is mixed with water ormiscible solvents such as propylene glycol, PEGs and ethanol, or an oilmedium, for example, peanut oil, liquid paraffin, or olive oil.

In one embodiment, the compounds of formula I and II may be administeredin chewable tablet compositions or soft chewable compositions such asthose described in US 2013/0203692 A1, US 2010/0087492, US 2006/0222684,US 2004/0151759, and U.S. Pat. No. 7,955,632, all incorporated herein byreference. The veterinary compositions may be in the form of a softchewable formulation (“soft chew”) which is palatable and acceptable tothe animal. In addition to the active ingredient(s), the soft chews ofthe invention may include one or more of the following components: asolvent or mixture of solvents, one or more fillers, one or morebinders, one or more surfactants, one or more humectants, one or morelubricants, one or more disintegrants, one or more colorants, one ormore antimicrobial agents, one or more antioxidants, one or more pHmodifiers and one or more flavoring agents.

Solvents that may be used in the compositions of the invention include,but are not limited to, various grades of liquid polyethylene glycol(PEG) including PEG 200, PEG 300, PEG 400 and PEG 540; propylenecarbonate; alcohols including ethanol, isopropanol and benzyl alcohol;propylene glycol; triglycerides including, but not limited to,caprylic/capric triglyceride, caprylic/capric/linoleic triglyceride(e.g., Miglyol® 810 and 812), caprylic/capric/succinic triglyceride,propylene glycol dicaprylate/dicaprate, and the like; water, sorbitolsolution, glycerol caprylate/caprate and polyglycolized glycerides(Gelucire®), or a combination thereof.

Various fillers known in the art may be used in the soft chewablecompositions of the invention. Fillers include, but are not limited to,corn starch, pre-gelatinized corn starch, soy protein fines, corn cob,and corn gluten meal, and the like. In some embodiments, a combinationof two or more fillers may be used in the compositions.

Binders that may be used in the compositions of the invention include,but are not limited to, polyvinylpyrrolidone (e.g., Povidone),cross-linked polyvinylpyrrolidone (Crospovidone), polyethylene glycolsof various grades including PEG 3350, PEG 4000, PEG 6000, PEG 8000 andeven PEG 20,000, and the like; co-polymers of vinylpyrrolidone and vinylacetate (e.g., Copovidone) such as the product sold by BASF by thetradename Kollidon® VA 64 and the like; starch such as potato starch,tapioca starch or corn starch; molasses, corn syrup, honey, maple syrupand sugars of various types; or a combination of two or more binders.

Humectants that may be used in the compositions include, but are notlimited to, glycerol (also referred to herein as glycerin), propyleneglycol, cetyl alcohol and glycerol monostearate, and the like.Polyethylene glycols of various grades may also be used as humectants.

Surfactants may be present in the composition to improve solubility andabsorption after ingestion. Surfactants are typically present in aconcentration of about 1 to 10% (w/w), more typically about 1 to about5% (w/w). Examples of surfactants that may be used in the compositionsinclude, but are not limited to, glyceryl monooleate, polyoxyethylenesorbitan fatty acid esters, sorbitan esters including sorbitanmonooleate (Span® 20), polyvinyl alcohol, polysorbates includingpolysorbate 20 and polysorbate 80, d-α2tocopheryl polyethylene glycol1000 succinate (TPGS), sodium lauryl sulfate, co-polymers of ethyleneoxide and propylene oxide (e.g., poloxamers such as Lutrol® F87 and thelike), polyethylene glycol castor oil derivatives including polyoxyl 35castor oil (Cremophor® EL), polyoxyl 40 hydrogenated castor oil(Cremophor® RH 40), polyoxyl 60 hydrogenated castor oil (Cremophor®RH60); propylene glycol monolaurate (Lauroglycol®); glyceride estersincluding glycerol caprylate/caprate (Capmul® MCM), polyglycolizedglycerides (Gelucire®), PEG 300 caprylic/capric glycerides (Softigen®767), PEG 400 caprylic/capric glycerides (Labrasol®), PEG 300 oleicglycerides (Labrafil® M-1944CS), PEG 300 linoleic glycerides (Labrafil®M-2125CS); polyethylene glycol stearates and polyethylene glycol hydroxystearates including polyoxyl 8 stearate (PEG 400 monostearate), polyoxyl40 stearate (PEG 1750 monostearate), and the like.

The inventive formulations may contain other inert ingredients such asantioxidants, preservatives, or pH stabilizers. These compounds are wellknown in the formulation art. Antioxidants may be added to thecompositions of the invention to inhibit degradation of the activeagents. Suitable antioxidants include, but are not limited to, alphatocopherol, ascorbic acid, ascorbyl palmitate, fumaric acid, malic acid,sodium ascorbate, sodium metabisulfate, n-propyl gallate, BHA (butylatedhydroxy anisole), BHT (butylated hydroxy toluene) monothioglycerol andthe like.

The compositions of the invention may also include one or morelubricants and/or processing aids. In some cases, thelubricant/processing aid may also behave as a solvent, and accordingly,some of the components of the inventive compositions may have dualfunctions. Lubricants/processing aids include, but are not limited to,polyethylene glycols of various molecular weight ranges including PEG3350 (Dow Chemical) and PEG 4000, corn oil, mineral oil, hydrogenatedvegetable oils (Stereotex or Lubritab), peanut oil and/or castor oil.

Many flavoring agents may be used in the compositions of the inventionto improve the palatability of the oral veterinary formulations.Preferred flavoring agents are those that are not derived from animalsources. In various embodiments, flavoring components derived fromfruit, meat (including, but not limited to, pork, beef, chicken, fish,poultry, and the like), vegetable, cheese, bacon, cheese-bacon and/orartificial flavorings may be used. A flavoring component is typicallychosen based upon consideration related to the animal that will beingesting the soft chew. For example, a horse may prefer an appleflavoring component, while a dog may prefer a meat flavoring component.Although flavoring components derived from non-animal sources arepreferred, in some embodiments, natural flavors containing beef or liverextracts, etc., may be used, such as braised beef flavor, artificialpowdered beef flavor, roast beef flavor and corned beef flavor amongothers.

In another embodiment of the invention, the active composition may beadministered via a drench, and may be administered either topically ororally. Drench formulations are those in which the liquid-containingcompositions of the invention are administered to the mouth or throat ofthe animal, or poured onto the skin or coat of the animal. The drenchformulations include a compound of formula I or formula II dissolved inan acceptable solvent, suspended in an acceptable medium or an emulsioncomprising the compound. Acceptable carriers will be known to those ofskill in the art and include, but are not limited to, water, oils,certain liquid polymers such as polyethylene glycols (PEGs). In oneembodiment, the drench formulations of the invention comprise a liquidpolyethylene glycol such as PEG 300 and/or PEG 400.

The compositions of the invention may also be in the form ofoil-in-water or water-in-oil emulsions. The oily phase maybe a vegetableoil, for example, olive oil or arachis oil, or a mineral oil, forexample, liquid paraffin or mixtures of these. Suitable emulsifyingagents include naturally-occurring phosphatides, for example, soy bean,lecithin, and esters or partial esters derived from fatty acids andhexitol anhydrides, for example, sorbitan monooleate, and condensationproducts of the said partial esters with ethylene oxide, for example,polyoxyethylene sorbitan monooleate. The emulsions may also containsweetening agents, bittering agents, flavoring agents, and/orpreservatives.

In one embodiment, the composition of the invention may be in the formof a microemulsion. Microemulsions are well suited as the liquid carriervehicle. Microemulsions are quaternary systems comprising an aqueousphase, an oily phase, a surfactant and a co-surfactant. They aretranslucent and isotropic liquids.

Microemulsions are composed of stable dispersions of microdroplets ofthe aqueous phase in the oily phase or conversely of microdroplets ofthe oily phase in the aqueous phase. The size of these microdroplets maybe less than 200 nm (1000 to 100,000 nm for emulsions). The interfacialfilm may be composed of an alternation of surface-active (SA) andco-surface-active (Co-SA) molecules which, by lowering the interfacialtension, allows the microemulsion to be formed spontaneously.

In one embodiment of the oily phase, the oily phase may be formed frommineral or vegetable oils, from unsaturated polyglycosylated glyceridesor from triglycerides, or alternatively from mixtures of such compounds.In one embodiment of the oily phase, the oily phase may be comprised oftriglycerides; in another embodiment of the oily phase, thetriglycerides are medium-chain triglycerides, for example C₈-C₁₀caprylic/capric triglyceride. In another embodiment of the oily phasemay represent a % v/v range of about 2 to about 15%; about 7 to about10%; and about 8 to about 9% v/v of the microemulsion.

The aqueous phase may include, for example water or glycol derivatives,such as propylene glycol, glycol ethers, polyethylene glycols orglycerol. In one embodiment, the glycol may be propylene glycol,diethylene glycol monoethyl ether, dipropylene glycol monoethyl ether ormixtures thereof. Generally, the aqueous phase will represent aproportion from about 1 to about 4% v/v in the microemulsion.

Surfactants for the microemulsion may include diethylene glycolmonoethyl ether, dipropylene glycol monomethyl ether, polyglycolyzedC₈-C₁₀ glycerides or polyglyceryl-6 dioleate. In addition to thesesurfactants, the co-surfactants may include short-chain alcohols, suchas ethanol and propanol.

Some compounds are common to the three components discussed above, i.e.,aqueous phase, surfactant and co-surfactant. However, it is well withinthe skill level of the practitioner to use different compounds for eachcomponent of the same formulation. In one embodiment for the amount ofsurfactant/co-surfactant, the co-surfactant to surfactant ratio will befrom about 1/7 to about 1/2. In another embodiment for the amount ofco-surfactant, there will be from about 25 to about 75% v/v ofsurfactant and from about 10 to about 55% v/v of co-surfactant in themicroemulsion.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example, arachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example, beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as sucrose, saccharinor aspartame, bittering agents, and flavoring agents may be added toprovide a palatable oral preparation. These compositions may bepreserved by the addition of an antioxidant such as ascorbic acid, orother known preservatives.

Aqueous suspensions may contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients include suspending agents, for example, sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents include naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample, heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide, with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agentsand/or bittering agents, such as those set forth above.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water may provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example, sweetening, bittering, flavoring andcoloring agents, may also be present.

Syrups and elixirs may be formulated with sweetening agents, forexample, glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative, flavoringagent(s) and/or coloring agent(s).

In another embodiment of the invention, the composition may be in pasteform. Examples of embodiments in a paste form include, but are notlimited to, those described in U.S. Pat. Nos. 6,787,342 and 7,001,889(each of which are incorporated herein by reference). In addition to thecompounds of the invention, the paste may further contain fumed silica;a viscosity modifier; a carrier; optionally, an absorbent; andoptionally, a colorant, stabilizer, surfactant, or preservative.

In one embodiment of the formulation, the formulation may be a pastecontaining the compounds of the invention, fumed silica, a viscositymodifier, an absorbent, a colorant; and a hydrophilic carrier which istriacetin, a monoglyceride, a diglyceride, or a triglyceride.

The paste may also include a viscosity modifier. Suitable viscositymodifiers include, but are not limited to, polyethylene glycols (PEG)including, but not limited to, PEG 200, PEG 300, PEG 400, PEG 600;monoethanolamine, triethanolamine, glycerol, propylene glycol,polyoxyethylene (20) sorbitan mono-oleate (polysorbate 80 or Tween 80),or poloxamers (e.g., Pluronic L 81); an absorbent such as magnesiumcarbonate, calcium carbonate, starch, and cellulose and its derivatives;and a colorant including, but not limited to, titanium dioxide ironoxide, or FD&C Blue #1 Aluminum Lake.

In some embodiments, the compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example, as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. Co-solventssuch as ethanol, propylene glycol, glycerol formal or polyethyleneglycols may also be used. Preservatives, such as phenol or benzylalcohol, may be used.

In addition, sterile, fixed oils may be conventionally employed as asolvent or suspending medium. For this purpose any bland fixed oil maybe employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

Topical, dermal and subdermal formulations may include, by way ofnon-limiting example, emulsions, creams, ointments, gels, pastes,powders, shampoos, pour-on formulations, ready-to-use formulations,spot-on solutions and suspensions, dips and sprays. Topical applicationof an inventive compound or of a composition including at least oneinventive compound among active agent(s) therein, in the form of aspot-on, spray-on or pour-on composition, may allow for the inventivecomposition to be absorbed through the skin to achieve systemic levels,distributed through the sebaceous glands or on the surface of the skinachieving levels throughout the coat. When the compound is distributedthrough the sebaceous glands, they may act as a reservoir, whereby theremay be a long-lasting effect (up to several months) effect. Spot-onformulations are typically applied in a localized region which refers toan area other than the entire animal. In one embodiment, the locationmay be between the shoulders. In another embodiment it may be a stripe,e.g., a stripe from head to tail of the animal.

Pour-on formulations are described in U.S. Pat. No. 6,010,710, alsoincorporated herein by reference. Pour-on formulations may beadvantageously oily, and generally comprise a diluent or vehicle andalso a solvent (e.g., an organic solvent) for the active ingredient ifthe latter is not soluble in the diluent.

Organic solvents that can be used in the invention include, but are notlimited to, acetyltributyl citrate, fatty acid esters such as thedimethyl ester, diisobutyl adipate, acetone, acetonitrile, benzylalcohol, ethyl alcohol, butyl diglycol, dimethylacetamide,dimethylformamide, dimethyl sulfoxide, dipropylene glycol n-butyl ether,ethanol, isopropanol, methanol, ethylene glycol monoethyl ether,ethylene glycol monomethyl ether, monomethylacetamide, dipropyleneglycol monomethyl ether, liquid polyoxyethylene glycols, propyleneglycol, 2-pyrrolidone (e.g., N-methylpyrrolidone), propylene carbonate,diethylene glycol monoethyl ether, ethylene glycol, triacetin, C₁-C₁₀esters of carboxylic acids such as butyl or octyl acetate, and diethylphthalate, or a mixture of at least two of these solvents.

The solvent will be used in proportion with the concentration of theactive agent compound and its solubility in this solvent. It will besought to have the lowest possible volume. The vehicle makes up thedifference to 100%.

A vehicle or diluent for the formulations may include dimethyl sulfoxide(DMSO), glycol derivatives such as, for example, propylene glycol,glycol ethers, polyethylene glycols or glycerol. As vehicle or diluent,mention may also be made of plant oils such as, but not limited tosoybean oil, groundnut oil, castor oil, corn oil, cotton oil, olive oil,grape seed oil, sunflower oil, etc.; mineral oils such as, but notlimited to, petrolatum, paraffin, silicone, etc.; aliphatic or cyclichydrocarbons or alternatively, for example, medium-chain (such as C₈ toC₁₂) triglycerides.

In another embodiment of the invention, an emollient and/or spreadingand/or film-forming agent may be added. In one embodiment, the emollientand/or spreading and/or film-forming agent may be:

polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetateand vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol,glycerol, sorbitol, polyoxyethylenated sorbitan esters; lecithin, sodiumcarboxymethylcellulose, silicone oils, polydiorganosiloxane oils (suchas polydimethylsiloxane (PDMS) oils), for example those containingsilanol functionalities, or a 45V2 oil,

anionic surfactants such as alkaline stearates, sodium, potassium orammonium stearates; calcium stearate, triethanolamine stearate; sodiumabietate; alkyl sulphates (e.g., sodium lauryl sulphate and sodium cetylsulphate); sodium dodecylbenzenesulphonate, sodiumdioctylsulphosuccinate; fatty acids (e.g., those derived from coconutoil),

cationic surfactants include water-soluble quaternary ammonium salts offormula N⁺R′R″R′″R″″, Y⁻ in which the radicals R are optionallyhydroxylated hydrocarbon radicals and Y⁻ is an anion of a strong acidsuch as the halide, sulphate and sulphonate anions;cetyltrimethylammonium bromide is among the cationic surfactants whichcan be used,

(a) amine salts of formula N⁺HR′R″R″ in which the radicals R areoptionally hydroxylated hydrocarbon radicals; octadecylaminehydrochloride is among the cationic surfactants which can be used,

(b) nonionic surfactants such as sorbitan esters, which are optionallypolyoxyethylenated (e.g., polysorbate 80), polyoxyethylenated alkylethers; polyoxypropylated fatty alcohols such as polyoxypropylene-styrolether; polyethylene glycol stearate, polyoxyethylenated derivatives ofcastor oil, polyglycerol esters, polyoxyethylenated fatty alcohols,polyoxyethylenated fatty acids, copolymers of ethylene oxide andpropylene oxide,(c) amphoteric surfactants such as the substituted lauryl compounds ofbetaine; or(d) a mixture of at least two of these agents.

In one embodiment of the amount of emollient, the emollient used may bein a proportion of from about 0.1 to 50% or 0.25 to 5%, by volume. Inanother embodiment, the emollient used may be in a proportion of fromabout 0.1% to about 30%, about 1% to about 30%, about 1% to about 20%,or about 5% to about 20% by volume.

In another embodiment of the invention, the composition may be inready-to-use solution form as is described in U.S. Pat. No. 6,395,765,incorporated herein by reference. In addition to the compounds of theinvention, the ready-to-use solution may contain a crystallizationinhibitor and an organic solvent or a mixture of organic solvents. Insome embodiments, water may be included with the organic solvent.

In various embodiments of the invention, the compositions may include acrystallization inhibitor in an amount of about 1 to about 50% (w/v) orabout 5 to about 40% (w/v) based on the total weight of the formulation.In other embodiments, the amount of crystallization inhibitor in theinventive formulations may be about 1% to about 30%, about 5% to about20%, about 1% to about 15%, or about 1% to about 10% (w/w). The type ofcrystallization inhibitor used in the inventive formulations is notlimited as long as it functions to inhibit crystallization of the activeor inactive agents from the formulation. For example, in certainembodiments of the invention, a solvent or co-solvent of the formulationmay also function as a crystallization inhibitor if it sufficientlyinhibits the formation of crystals from forming over time when theformulation is administered.

Crystallization inhibitors which are useful for the invention include,but are not limited to: polyvinylpyrrolidone, polyvinyl alcohols,copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycols,benzyl alcohol, dimethylformamide, dimethylacetamide, dimethylsulfoxide,2-pyrrolidone, N-methylpyrrolidone, mannitol, glycerol, sorbitol orpolyoxyethylenated esters of sorbitan; lecithin or sodiumcarboxymethylcellulose; or acrylic derivatives, such as acrylates ormethacrylates or polymers or copolymers thereof, polyethyleneglycols(PEG) or polymers containing polyethyleneglycols, such as glycofurol andthe like, and others;

anionic surfactants, such as alkaline stearates (e.g., sodium, potassiumor ammonium stearate); calcium stearate or triethanolamine stearate;sodium abietate; alkyl sulphates, which include but are not limited tosodium lauryl sulphate and sodium cetyl sulphate; sodiumdodecylbenzenesulphonate or sodium dioctyl sulphosuccinate; or fattyacids (e.g., coconut oil);

cationic surfactants, such as water-soluble quaternary ammonium salts offormula N′R′R″R′″R″″Y⁻, in which the R radicals are identical ordifferent optionally hydroxylated hydrocarbon radicals and Y⁻ is ananion of a strong acid, such as halide, sulphate and sulphonate anions;cetyltrimethylammonium bromide is one of the cationic surfactants whichcan be used;

amine salts of formula N⁺HR′R″R′″, in which the R radicals are identicalor different optionally hydroxylated hydrocarbon radicals;octadecylamine hydrochloride is one of the cationic surfactants whichcan be used;

non-ionic surfactants, such as optionally polyoxyethylenated esters ofsorbitan, e.g., Polysorbate 80, or polyoxyethylenated alkyl ethers;polyethylene glycol stearate, polyoxyethylenated derivatives of castoroil, polyglycerol esters, polyoxyethylenated fatty alcohols,polyoxyethylenated fatty acids or copolymers of ethylene oxide and ofpropylene oxide;

amphoteric surfactants, such as substituted lauryl compounds of betaine;

a mixture of at least two of the compounds listed in (a)-(f) above; or

an organic solvent or mixture of solvents which inhibit the formation ofcrystals or amorphous solid after the formulation is administered.

In one embodiment of the crystallization inhibitor, a crystallizationinhibitor pair will be used. Such pairs include, for example, thecombination of a film-forming agent of polymeric type and of asurface-active agent. These agents will be selected from the compoundsmentioned above as crystallization inhibitor.

In some embodiments, the organic solvent(s) may have a dielectricconstant of between about 10 and about 35 or between about 20 and about30. In other embodiments, the organic solvent may have a dielectricconstant of between about 10 and about 40 or between about 20 and about30. The content of this organic solvent or mixture of solvents in theoverall composition is not limited and will be present in an amountsufficient to dissolve the desired components to a desiredconcentration. As discussed above, the organic solvent may also functionas a crystallization inhibitor in the formulation.

In some embodiments, one or more of the organic solvent(s) may have aboiling point of below about 100° C., or below about 80° C. In otherembodiments, the organic solvent(s) may have a boiling point of belowabout 300° C., below about 250° C., below about 230° C., below about210° C. or below about 200° C.

In some embodiments where there is a mixture of solvents, i.e. a solventand a co-solvent, the solvents may be present in the composition in aweight/weight (W/W) ratio of about 1/50 to about 1/1. Typically thesolvents will be in a ratio of about 1/30 to about 1/1, about 1/20 toabout 1/1, or about 1/15 to about 1/1 by weight. Preferably, the twosolvents will be present in a weight/weight ratio of about 1/15 to about1/2. In some embodiments, at least one of the solvents present may actas to improve solubility of the active agent or as a drying promoter. Inparticular embodiments, at least one of the solvents will be misciblewith water.

The formulation may also comprise an antioxidizing agent intended toinhibit oxidation in air, this agent may be present in a proportion ofabout 0.005 to about 1% (w/v), about 0.01 to about 0.1%, or about 0.01to about 0.05%.

In one embodiment of the film-forming agent, the agents are of thepolymeric type, which include but are not limited to the various gradesof polyvinylpyrrolidone, polyvinyl alcohols, and copolymers of vinylacetate and of vinylpyrrolidone.

In one embodiment of the surface-active agents, the agents include butare not limited to those made of non-ionic surfactants; in anotherembodiment of the surface active agents, the agent is apolyoxyethylenated esters of sorbitan and in yet another embodiment ofthe surface-active agent, the agents include the various grades ofpolysorbate, for example Polysorbate 80.

In another embodiment of the invention, the film-forming agent and thesurface-active agent may be incorporated in similar or identical amountswithin the limit of the total amounts of crystallization inhibitormentioned elsewhere.

The crystallization inhibitor inhibits the formation of crystals on thecoat, and improves the maintenance of the cosmetic appearance of theskin or fur; that is to say without a tendency towards sticking ortowards a sticky appearance, despite the high concentration of activematerial. Substances other than those mentioned herein may be used ascrystallization inhibitors in the present invention. In one embodiment,the effectiveness of the crystallization inhibitor may be demonstratedby a test according to which 0.3 mL of a solution comprising 10% (w/v)of the active agent in an appropriate solvent as defined above, and 10%(w/v) of the compound acting as a crystallization inhibitor are placedon a glass slide at 20° C. for 24 hours, after which fewer than 10crystals, preferably 0 crystals, are seen with the naked eye on theglass slide.

In one embodiment of the antioxidizing agents, the agents are thoseconventional in the art and include but are not limited to butylatedhydroxyanisole, butylated hydroxytoluene, ascorbic acid, sodiummetabisulphite, propyl gallate, sodium thiosulphate or a mixture of atleast two compounds with antioxidant properties.

The formulation adjuvants discussed above are well known to thepractitioner in this art and may be obtained commercially or throughknown techniques. These concentrated compositions are generally preparedby simple mixing of the constituents as defined above; advantageously,the starting point is to mix the active material in the main solvent andthen the other ingredients or adjuvants are added.

The volume of the formulation applied will depend on the type of animaland the size of the animal as well as the strength of the formulationand the potency of the active agents. In one embodiment, an amount ofabout 0.1 to about 20 ml of the formulation may be applied to theanimal. In other embodiment for the volume, the volume may be about 0.1to about 10 ml, about 0.1 to about 5 ml, about 0.5 ml to about 10 ml, orabout 0.3 to about 3 ml.

In another embodiment of the invention, application of a spot-onformulation according to the present invention may also providelong-lasting and broad-spectrum efficacy when the solution is applied tothe mammal or bird. The spot-on formulations provide for topicaladministration of a concentrated solution, suspension, microemulsion oremulsion for intermittent application to a spot on the animal, generallybetween the two shoulders (solution of spot-on type).

For spot-on formulations, the carrier may be a liquid carrier vehicle asdescribed in U.S. Pat. No. 6,426,333 (incorporated herein by reference),which in one embodiment of the spot-on formulation may comprise asolvent or mixture of solvents including, but not limited to, acetone,an aliphatic alcohol such as methanol, ethanol, propanol, butanol,isopropanol, pentanol, hexanol, heptanol, octanol, nonanol,cyclopentanol, cyclohexanol, ethylene glycol, propylene glycol and thelike; an aromatic alcohol such as phenol, cresol, naphthol, benzylalcohol and the like; acetonitrile, butyl diglycol, an organic amidesuch as dimethylacetamide, dimethylformamide, monomethylacetamide,2-pyrrolidone, N-methylpyrrolidone, vinylpyrrolidone and the like;propylene or ethylene carbonate, dimethylsulfoxide (DMSO), a glycolpolymer or an ether thereof, such as polyethylene glycol (PEG) ofvarious grades, polypropylene glycols of various grades, dipropyleneglycol n-butyl ether, ethylene glycol monoethyl ether, ethylene glycolmonomethyl ether, dipropylene glycol monomethyl ether, diethylene glycolmonoethyl ether, ethylene glycol, diethyl phthalate fatty acid esters,such as the diethyl ester or diisobutyl adipate, or a mixture of atleast two of these solvents.

The liquid carrier vehicle may optionally contain a crystallizationinhibitor including, but not limited to, those described in (a) to (h)above, or a compound that may act both as a solvent and acrystallization inhibitor (as defined above), or a mixture of thesecrystallization inhibitors.

Spot-on formulations may be prepared by dissolving the activeingredients into the pharmaceutically or veterinary acceptable vehicle.Alternatively, the spot-on formulation may be prepared by encapsulationof the active ingredient to leave a residue of the therapeutic agent onthe surface of the animal. These formulations will vary with regard tothe weight of the therapeutic agent in the combination depending on thespecies of host animal to be treated, the severity and type of infectionand the body weight of the host.

Dosage forms may typically contain from about 0.1 mg to about 5 g. Inother embodiments, the dosage form may contain about 0.5 mg to about 5 gof an active agent. In one embodiment of the dosage form, the dosage maycontain from about 1 mg to about 500 mg of an active agent, typicallyabout 25 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg,about 400 mg, about 500 mg, about 600 mg, about 800 mg, or about 1000mg.

In one embodiment of the invention, the compound of formula I or formulaII may be present in the formulation at a concentration of about 0.05 toabout 10% weight/volume. In one embodiment, the compound is present in aconcentration of about 2 to about 5% (w/v). In another embodiment, thecompound is present in a concentration of about 3 to about 6% (w/v). Inanother embodiment of the invention, the active agent may be present inthe formulation as a concentration from about 0.1 to about 2%weight/volume. In yet another embodiment of the invention, the activeagent may be present in the formulation as a concentration from about0.25 to about 1.5% weight/volume. In still another embodiment of theinvention, the active agent may be present in the formulation as aconcentration about 1% weight/volume.

In one embodiment, the composition comprises a compound of formula I orformula II that is substantially enriched in an enantiomer. The term“substantially enriched” is meant wherein the weight:weight ratio is atleast about 1.5:1 or higher in favor of the desired enantiomer. Inanother embodiment, the extended release injectable compositionscomprise a compound of formula I or formula II, that is substantiallyenriched in the (S)-enantiomer. In another embodiment, the extendedrelease injectable compositions comprise a compound of formula I orformula II that is substantially enriched in the (R)-enantiomer.

In another embodiment, the compositions comprise a compound of formula Ior formula II, that is enriched in the (S)-enantiomer in a weight:weightratio of at least about 2:1, (S) to (R), or greater. In yet anotherembodiment, the compositions comprise a compound of formula I or formulaII that is enriched in the (S)-enantiomer in a weight:weight ratio of atleast about 5:1, (S) to (R), or greater. In still another embodiment,the compositions of the invention comprise a compound of formula I orformula II, that is enriched in the (S)-enantiomer in a weight:weightratio of at least about 10:1, (S) to (R), or greater. In still anotherembodiment, the compositions comprise a compound of formula I or formulaII, that is essentially the pure (S)-enantiomer.

In another embodiment, the compositions comprise a compound of formula Ior formula II, that is enriched in the (R)-enantiomer in a weight:weightratio is at least approximately 2:1, (R) to (S), or greater. In yetanother embodiment, the compositions of the invention comprise acompound of formula I or formula II, that is enriched in the(R)-enantiomer in a weight:weight ratio of at least about 5:1, (R) to(S), or greater. In still another embodiment, the compositions of theinvention comprise a compound of formula I or formula II, that isenriched in the (R)-enantiomer in a weight:weight ratio of at leastabout 10:1, (R) to (S), or greater. In still another embodiment, thecompositions of the invention comprise a compound of formula I orformula II that is essentially the pure R-enantiomer.

Veterinary Methods and Uses

Another embodiment of the disclosure is directed toward a method oftreating endoparasiticidal infection in a mammal in need thereof whichcomprising administering an effective amount of the compound of thedisclosure.

In one embodiment for treating endoparasiticidal infection is that thehelminth is selected from the group consisting of but not limited toAnaplocephaela (Anoplocephala), Ancylostoma, Anecator, Ascaris, Brugia,Bunostomum, Capillaria, Chabertia, Cooperia, Cyathostomum, Cylicocyclus,Cylicodontophorus, Cylicostephanus, Craterostomum, Dictyocaulus,Dipetalonema, Dipylidium, Dirofilaria, Dracunculus, Echinococcus,Enterobius, Fasciola, Filaroides, Habronema, Haemonchus, Metastrongylus,Moniezia, Necator, Nematodirus, Nippostrongylus, Oesophagostumum,Onchocerca, Ostertagia, Oxyuris, Paracaris, Schistosoma, Strongylus,Taenia, Toxocara, Strongyloides, Toxascaris, Trichinella, Trichuris,Trichostrongylus, Triodontophorous, Uncinaria, Wuchereria, andcombinations thereof.

In another embodiment of the disclosure, the helminth is Haemonchuscontortus, Ostertagia circumcincta, Trichostrongylus axei,Trichostrongylus colubriformis, Cooperia curticei, Nematodirus battusand combinations thereof.

In one embodiment, resistant strains of the organisms above may becontrolled according to the disclosure. In an embodiment, the methodsand uses of the invention are effective against endoparasites that arenot effectively controlled by macrocyclic lactones such as avermectinsand milbemycins. In another embodiment, the methods and uses of theinvention are effective against endoparasites that are resistant tobenzimidazole active agents.

Another embodiment of the disclosure is directed toward a method oftreating ectoparasiticidal infection in a mammal in need thereof, whichcomprises administering an effective amount of the compound of thedisclosure.

In one embodiment for treating ectoparasiticidal infection, the infectedis selected from the group consisting of but not limited to fleas,ticks, mites, mosquitoes, flies, lice, blowfly and combinations thereof.

In another embodiment, the compositions comprising formula I and/or IIcompounds may also include other veterinary therapeutic agents.Veterinary pharmaceutical agents that may be included in thecompositions of the invention are well-known in the art (see e.g.,Plumb' Veterinary Drug Handbook, 5^(th) Edition, ed. Donald C. Plumb,Blackwell Publishing, (2005) or The Merck Veterinary Manual, 9^(th)Edition, (January 2005)) and include but are not limited to acarbose,acepromazine maleate, acetaminophen, acetazolamide, acetazolamidesodium, acetic acid, acetohydroxamic acid, acetylcysteine, acitretin,acyclovir, albendazole, albuterol sulfate, alfentanil, allopurinol,alprazolam, altrenogest, amantadine, amikacin sulfate, aminocaproicacid, aminopentamide hydrogen sulfate, aminophylline/theophylline,amiodarone, amitriptyline, amlodipine besylate, ammonium chloride,ammonium molybdate, amoxicillin, clavulanate potassium, amphotericin Bdeoxycholate, amphotericin B lipid-based, ampicillin, amprolium,antacids (oral), antivenin, apomorphione, apramycin sulfate, ascorbicacid, asparaginase, aspiring, atenolol, atipamezole, atracuriumbesylate, atropine sulfate, auranofin, aurothioglucose, azaperone,azathioprine, azithromycin, baclofen, barbiturates, benazepril,betamethasone, bethanechol chloride, bisacodyl, bismuth sub salicylate,bleomycin sulfate, boldenone undecylenate, bromides, bromocriptinemesylate, budesonide, buprenorphine, buspirone, busulfan, butorphanoltartrate, cabergoline, calcitonin salmon, calcitrol, calcium salts,captopril, carbenicillin indanyl sodium, carbimazole, carboplatin,carnitine, carprofen, carvedilol, cefadroxil, cefazolin sodium,cefixime, clorsulon, cefoperazone sodium, cefotaxime sodium, cefotetandisodium, cefoxitin sodium, cefpodoxime proxetil, ceftazidime, ceftiofursodium, ceftiofur, ceftriaxone sodium, cephalexin, cephalosporins,cephapirin, charcoal (activated), chlorambucil, chloramphenicol,chlordiazepoxide, chlordiazepoxide+/−clidinium bromide, chlorothiazide,chlorpheniramine maleate, chlorpromazine, chlorpropamide,chlortetracycline, chorionic gonadotropin (HCG), chromium, cimetidine,ciprofloxacin, cisapride, cisplatin, citrate salts, clarithromycin,clemastine fumarate, clenbuterol, clindamycin, clofazimine,clomipramine, claonazepam, clonidine, cloprostenol sodium, clorazepatedipotassium, clorsulon, cloxacillin, codeine phosphate, colchicine,corticotropin (ACTH), cosyntropin, cyclophosphamide, cyclosporine,cyproheptadine, cytarabine, dacarbazine, dactinomycin/actinomycin D,dalteparin sodium, danazol, dantrolene sodium, dapsone, decoquinate,deferoxamine mesylate, deracoxib, deslorelin acetate, desmopressinacetate, desoxycorticosterone pivalate, detomidine, dexamethasone,dexpanthenol, dexraazoxane, dextran, diazepam, diazoxide (oral),dichlorphenamide, diclofenac sodium, dicloxacillin, diethylcarbamazinecitrate, diethylstilbestrol (DES), difloxacin, digoxin,dihydrotachysterol (DHT), diltiazem, dimenhydrinate, dimercaprol/BAL,dimethyl sulfoxide, dinoprost tromethamine, diphenylhydramine,disopyramide phosphate, dobutamine, docusate/DSS, dolasetron mesylate,domperidone, dopamine, doramectin, doxapram, doxepin, doxorubicin,doxycycline, edetate calcium disodium.calcium EDTA, edrophoniumchloride, enalapril/enalaprilat, enoxaparin sodium, enrofloxacin,ephedrine sulfate, epinephrine, epoetin/erythropoietin, eprinomectin,epsiprantel, erythromycin, esmolol, estradiol cypionate, ethacrynicacid/ethacrynate sodium, ethanol (alcohol), etidronate sodium, etodolac,etomidate, euthanasia agents w/pentobarbital, famotidine, fatty acids(essential/omega), felbamate, fentanyl, ferrous sulfate, filgrastim,finasteride, fipronil, florfenicol, fluconazole, flucytosine,fludrocortisone acetate, flumazenil, flumethasone, flunixin meglumine,fluorouracil (5-FU), fluoxetine, fluticasone propionate, fluvoxaminemaleate, fomepizole (4-MP), furazolidone, furosemide, gabapentin,gemcitabine, gentamicin sulfate, glimepiride, glipizide, glucagon,glucocorticoid agents, glucosamine/chondroitin sulfate, glutamine,glyburide, glycerine (oral), glycopyrrolate, gonadorelin, grisseofulvin,guaifenesin, halothane, hemoglobin glutamer-200 (OXYGLOBIN®®), heparin,hetastarch, hyaluronate sodium, hydrazaline, hydrochlorothiazide,hydrocodone bitartrate, hydrocortisone, hydromorphone, hydroxyurea,hydroxyzine, ifosfamide, imidacloprid, imidocarb dipropinate,impenem-cilastatin sodium, imipramine, inamrinone lactate, insulin,interferon alfa-2a (human recombinant), iodide (sodium/potassium),ipecac (syrup), ipodate sodium, iron dextran, isoflurane, isoproterenol,isotretinoin, isoxsuprine, itraconazole, ivermectin, kaolin/pectin,ketamine, ketoconazole, ketoprofen, ketorolac tromethamine, lactulose,leuprolide, levamisole, levetiracetam, levothyroxine sodium, lidocaine,lincomycin, liothyronine sodium, lisinopril, lomustine (CCNU),lufenuron, lysine, magnesium, mannitol, marbofloxacin, mechlorethamine,meclizine, meclofenamic acid, medetomidine, medium chain triglycerides,medroxyprogesterone acetate, megestrol acetate, melarsomine, melatonin,meloxican, melphalan, meperidine, mercaptopurine, meropenem, metformin,methadone, methazolamide, methenamine mandelate/hippurate, methimazole,methionine, methocarbamol, methohexital sodium, methotrexate,methoxyflurane, methylene blue, methylphenidate, methylprednisolone,metoclopramide, metoprolol, metronidaxole, mexiletine, mibolerlone,midazolam milbemycin oxime, mineral oil, minocycline, misoprostol,mitotane, mitoxantrone, morphine sulfate, moxidectin, naloxone,mandrolone decanoate, naproxen, narcotic (opiate) agonist analgesics,neomycin sulfate, neostigmine, niacinamide, nitazoxanide, nitenpyram,nitrofurantoin, nitroglycerin, nitroprusside sodium, nizatidine,novobiocin sodium, nystatin, octreotide acetate, olsalazine sodium,omeprozole, ondansetron, opiate antidiarrheals, orbifloxacin, oxacillinsodium, oxazepam, oxibutynin chloride, oxymorphone, oxytretracycline,oxytocin, pamidronate disodium, pancreplipase, pancuronium bromide,paromomycin sulfate, parozetine, pencillamine, general informationpenicillins, penicillin G, penicillin V potassium, pentazocine,pentobarbital sodium, pentosan polysulfate sodium, pentoxifylline,pergolide mesylate, phenobarbital, phenoxybenzamine, pheylbutazone,phenylephrine, phenypropanolamine, phenytoin sodium, pheromones,parenteral phosphate, phytonadione/vitamin K-1, pimobendan, piperazine,pirlimycin, piroxicam, polysulfated glycosaminoglycan, ponazuril,potassium chloride, pralidoxime chloride, prazosin,prednisolone/prednisone, primidone, procainamide, procarbazine,prochlorperazine, propantheline bromide, Propionibacterium acnesinjection, propofol, propranolol, protamine sulfate, pseudoephedrine,psyllium hydrophilic mucilloid, pyridostigmine bromide, pyrilaminemaleate, pyrimethamine, quinacrine, quinidine, ranitidine, rifampin,s-adenosyl-methionine (SAMe), saline/hyperosmotic laxative, selamectin,selegiline/l-deprenyl, sertraline, sevelamer, sevoflurane,silymarin/milk thistle, sodium bicarbonate, sodium polystyrenesulfonate, sodium stibogluconate, sodium sulfate, sodium thiosulfate,somatotropin, sotalol, spectinomycin, spironolactone, stanozolol,streptokinase, streptozocin, succimer, succinylcholine chloride,sucralfate, sufentanil citrate, sulfachlorpyridazine sodium,sulfadiazine/trimethroprim, sulfamethoxazole/trimethoprim,sulfadimentoxine, sulfadimethoxine/ormetoprim, sulfasalazine, taurine,tepoxaline, terbinafline, terbutaline sulfate, testosterone,tetracycline, thiacetarsamide sodium, thiamine, thioguanine, thiopentalsodium, thiotepa, thyrotropin, tiamulin, ticarcilin disodium,tiletamine/zolazepam, tilmocsin, tiopronin, tobramycin sulfate,tocainide, tolazoline, telfenamic acid, topiramate, tramadol,trimcinolone acetonide, trientine, trilostane, trimepraxine tartratew/prednisolone, tripelennamine, tylosin, urdosiol, valproic acid,vanadium, vancomycin, vasopressin, vecuronium bromide, verapamil,vinblastine sulfate, vincristine sulfate, vitamin E/selenium, warfarinsodium, xylazine, yohimbine, zafirlukast, zidovudine (AZT), zincacetate/zinc sulfate, zonisamide and mixtures thereof.

In one embodiment of the invention, arylpyrazole compounds such asphenylpyrazoles may be included in the veterinary compositions of theinvention. Arylpyrazoles are known in the art and are suitable forcombination with the compounds of formula I or formula II in thecompositions of the invention. Examples of such arylpyrazole compoundsinclude but are not limited to those described in U.S. Pat. Nos.6,001,384; 6,010,710; 6,083,519; 6,096,329; 6,174,540; 6,685,954,6,998,131 and 7,759,381 (all of which are incorporated herein byreference). A particularly preferred arylpyrazole active agent isfipronil.

In another embodiment of the invention, one or more macrocycliclactones, which act as an acaricide, an anthelmintic agent and/or aninsecticide, can be included in the compositions of the invention incombination with the compounds of formula I or formula II. For theavoidance of doubt, the term “macrocyclic lactone” as used hereinincludes both naturally occurring and synthetic or semi-syntheticavermectin and milbemycin compounds. It has been found that combinationsof a compound of formula I or formula II with an avermectin ormilbemycin active agent are particularly effective in controllingendoparasites that are difficult to control with avermectins ormilbemycin alone.

The macrocyclic lactones that may be used in the compositions of theinvention include, but are not limited to, the naturally producedavermectins (e.g., including the components designated as A₁a, A₁b, A₂a,A₂b, B₁a, B₁b, B₂a and B₂b) and milbemycin compounds, semisyntheticavermectins and milbemycins, avermectin monosaccharide compounds andavermectin aglycone compounds. Examples of macrocyclic lactone compoundsthat may be used in the compositions include, but are not limited to,abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin,latidectin, lepimectin, selamectin, ML-1,694,554 and milbemycinsincluding, but not limited to, milbemectin, milbemycin D, milbemycin A₃,milbemycin A₄, milbemycin oxime, moxidectin and nemadectin. Alsoincluded are the 5-oxo and 5-oxime derivatives of said avermectins andmilbemycins.

The macrocyclic lactone compounds are known in the art and can easily beobtained commercially or through synthesis techniques known in the art.Reference is made to the widely available technical and commercialliterature. For avermectins, ivermectin and abamectin, reference may bemade, for example, to the work “Ivermectin and Abamectin”, 1989, by M.H. Fischer and H. Mrozik, William C. Campbell, published by SpringerVerlag., or Albers-Schönberg et al. (1981), “Avermectins StructureDetermination”, J. Am. Chem. Soc., 103, 4216-4221. For doramectin,“Veterinary Parasitology”, vol. 49, No. 1, July 1993, 5-15 may beconsulted. For milbemycins, reference may be made, inter alia, to DaviesH. G. et al., 1986, “Avermectins and Milbemycins”, Nat. Prod. Rep., 3,87-121, Mrozik H. et al., 1983, Synthesis of Milbemycins fromAvermectins, Tetrahedron Lett., 24, 5333-5336, U.S. Pat. No. 4,134,973and EP 0 677 054.

Macrocyclic lactones are either natural products or are semi-syntheticderivatives thereof. The structure of the avermectins and milbemycinsare closely related, e.g., by sharing a complex 16-membered macrocycliclactone ring. The natural product avermectins are disclosed in U.S. Pat.No. 4,310,519 and the 22,23-dihydro avermectin compounds are disclosedin U.S. Pat. No. 4,199,569 (both incorporated herein by reference).Mention is also made of U.S. Pat. Nos. 4,468,390, 5,824,653, EP 0 007812 A1, U.K. Patent Specification 1 390 336, EP 0 002 916, and NewZealand Patent No. 237 086 (all incorporated by reference), inter alia.Naturally occurring milbemycins are described in U.S. Pat. No.3,950,360, which is incorporated herein by reference, as well as in thevarious references cited in “The Merck Index” 12^(th) ed., S. Budavari,Ed., Merck & Co., Inc. Whitehouse Station, N.J. (1996). Latidectin isdescribed in the “International Nonproprietary Names for PharmaceuticalSubstances (INN)”, WHO Drug Information, vol. 17, no. 4, pp. 263-286,(2003). Semisynthetic derivatives of these classes of compounds are wellknown in the art and are described, for example, in U.S. Pat. Nos.5,077,308, 4,859,657, 4,963,582, 4,855,317, 4,871,719, 4,874,749,4,427,663, 4,310,519, 4,199,569, 5,055,596, 4,973,711, 4,978,677,4,920,148 and EP 0 667 054 (all incorporated by reference).

In another embodiment, compound I or compound II may be combined with aclass of compounds known as insect growth regulators (IGRs). Compoundsbelonging to this group are well known to the practitioner and representa wide range of different chemical classes. These compounds all act byinterfering with the development or growth of the insect pests. Insectgrowth regulators are described, for example, in U.S. Pat. Nos.3,748,356, 3,818,047, 4,225,598, 4,798,837, 4,751,225, EP 0 179 022 orU.K. 2 140 010 as well as U.S. Pat. Nos. 6,096,329 and 6,685,954 (allincorporated herein by reference).

In one embodiment, the IGR is a compound that mimics juvenile hormone.Examples of juvenile hormone mimics include azadirachtin, diofenolan,fenoxycarb, hydroprene, kinoprene, methoprene, pyriproxyfen,tetrahydroazadirachtin and4-chloro-2(2-chloro-2-methyl-propyl)-5-(6-iodo-3-pyridylmethoxy)pyridazine-3(2H)-one.

In another embodiment, the IGR compound is a chitin synthesis inhibitor.Chitin synthesis inhibitors include chlorfluazuron, cyromazine,diflubenzuron, fluazuron, flucycloxuron, flufenoxuron, hexaflumuron,lufenuron, tebufenozide, teflubenzuron, triflumoron, novaluron,1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(trifluoromethyl)phenylurea,1-(2,6-difluoro-benzoyl)-3-(2-fluoro-4-(1,1,2,2-tetrafluoroethoxy)-phenylureaand 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-trifluoromethyl)phenylurea.

In yet another embodiment of the invention, adulticide insecticides andacaricides can also be combined with compound I or compound II. Theseinclude pyrethrins (which include cinerin I, cinerin II, jasmolin I,jasmolin II, pyrethrin I, pyrethrin II and mixtures thereof) andpyrethroids (including permethrin cyhalothrin, cypermethrin,deltamethrin, fenvalerate, flucythrinate), and carbamates including, butare not limited to, benomyl, carbanolate, carbaryl, carbofuran,meththiocarb, metolcarb, promacyl, propoxur, aldicarb, butocarboxim,oxamyl, thiocarboxime and thiofanox.

In some embodiments, compound I or compound II may be combined with oneor more antinematodal agents including, but not limited to, activeagents in the benzimidazoles, imidazothiazoles, tetrahydropyrimidines,and organophosphate class of compounds. In some embodiments,benzimidazoles including, but not limited to, thiabendazole,cambendazole, parbendazole, oxibendazole, mebendazole, flubendazole,fenbendazole, oxfendazole, albendazole, cyclobendazole, febantel,thiophanate and its o,o-dimethyl analogue may be included in thecompositions.

In other embodiments, compound I or compound II may be combined with animidazothiazole compounds including, but not limited to, tetramisole,levamisole and butamisole. In still other embodiments, the isoxazolinecompounds of the invention may be combined with tetrahydropyrimidineactive agents including, but not limited to, pyrantel, oxantel, andmorantel. Suitable organophosphate active agents include, but are notlimited to, coumaphos, trichlorfon, haloxon, naftalofos and dichlorvos,heptenophos, mevinphos, monocrotophos, TEPP, and tetrachlorvinphos.

In other embodiments, compound I or compound II may be combined with theantinematodal compounds phenothiazine and piperazine as the neutralcompound, or in various salt forms, diethylcarbamazine, phenols such asdisophenol, arsenicals such as arsenamide, ethanolamines such asbephenium, thenium closylate, and methyridine; cyanine dyes includingpyrvinium chloride, pyrvinium pamoate and dithiazanine iodide;isothiocyanates including bitoscanate, suramin sodium, phthalofyne, andvarious natural products including, but not limited to, hygromycin B,α-santonin and kainic acid.

In other embodiments, compound I or compound II may be combined withantitrematodal agents. Suitable antitrematodal agents include, but arenot limited to, the miracils such as miracil D and mirasan;praziquantel, clonazepam and its 3-methyl derivative, oltipraz,lucanthone, hycanthone, oxamniquine, amoscanate, niridazole, nitroxynil,various bisphenol compounds known in the art including hexachlorophene,bithionol, bithionol sulfoxide and menichlopholan; varioussalicylanilide compounds including tribromsalan, oxyclozanide,clioxanide, rafoxanide, brotianide, bromoxanide and closantel;triclabendazole, diamfenetide, clorsulon, hetolin and emetine.

Anticestodal compounds may also be advantageously combined with compoundI or compound II including, but not limited to, arecoline in varioussalt forms, bunamidine, niclosamide, nitroscanate, paromomycin andparomomycin II.

In yet other embodiments, compound I or compound II may be combined withother active agents that are effective against arthropod parasites.Suitable active agents include, but are not limited to, bromocyclen,chlordane, DDT, endosulfan, lindane, methoxychlor, toxaphene, bromophos,bromophos-ethyl, carbophenothion, chlorfenvinphos, chlorpyrifos,crotoxyphos, cythioate, diazinon, dichlorenthion, diemthoate,dioxathion, ethion, famphur, fenitrothion, fenthion, fospirate,iodofenphos, malathion, naled, phosalone, phosmet, phoxim, propetamphos,ronnel, stirofos, allethrin, cyhalothrin, cypermethrin, deltamethrin,fenvalerate, flucythrinate, permethrin, phenothrin, pyrethrins,resmethrin, benzyl benzoate, carbon disulfide, crotamiton,diflubenzuron, diphenylamine, disulfiram, isobornyl thiocyanato acetate,methoprene, monosulfiram, pirenonylbutoxide, rotenone, triphenyltinacetate, triphenyltin hydroxide, deet, dimethyl phthalate, and thecompounds 1,5a,6,9,9a,9b-hexahydro-4a(4H)-dibenzofurancarboxaldehyde(MGK-11),2-(2-ethylhexyl)-3a,4,7,7a-tetrahydro-4,7-methano-1H-isoindole-1,3(2H)dione(MGK-264), dipropyl-2,5-pyridinedicarboxylate (MGK-326) and2-(octylthio)ethanol (MGK-874).

In another embodiment, compound I or compound II may be combined withpyrethroid active agents including, but not limited to, permethrin,deltamethrin, cypermethrin, cyphenothrin, etofenprox, fenvalerate andcyfluthrin.

Another antiparasitic agent that can be combined with compound I orcompound II includes a biologically active peptide or protein including,but not limited to, depsipeptides, which act at the neuromuscularjunction by stimulating presynaptic receptors belonging to the secretinreceptor family resulting in the paralysis and death of parasites. Inone embodiment, the depsipeptide is emodepside (see Willson et al.,Parasitology, January 2003, 126(Pt 1):79-86).

In another embodiment, compound I or compound II may be combined with anactive agent from the neonicotinoid class of pesticides. Theneonicotinoids bind and inhibit insect specific nicotinic acetylcholinereceptors. In one embodiment, the neonicotinoid insecticidal agent isimidacloprid. Imidacloprid is a well-known neonicotinoid active agentand is the key active ingredient in the topical parasiticide productsAdvantage®, Advantage® II, K9 Advantix®, and K9 Advantix® II sold byBayer Animal Health. Agents of this class are described, for example, inU.S. Pat. No. 4,742,060 or in EP 0 892 060 (incorporated herein byreference).

In another embodiment, the neonicotinoid active agent is nitenpyram.Nitenpyram is the active ingredient in the oral product CAPSTAR™ Tabletssold by Novartis Animal Health.

Nitenpyram is active against adult fleas when given daily as an oraltablet. Nitenpyram works by interfering with normal nerve transmissionand leads to the death of the insect. Nitenpyram has a very fast onsetof action against fleas. For example, CAPSTAR™ Tablets begin to actagainst fleas in as early as 30 minutes after administration and isindicated for use as often as once a day.

In certain embodiments, an insecticidal agent that can be combined withcompound I or compound II is a semicarbazone, such as metaflumizone.

In another embodiment, compound I or compound II may advantageously becombined with an isoxazoline compound known in the art. The isoxazolineactive agents are systemically-acting active agents that are highlyeffective against ectoparasites. These active agents are described inU.S. Pat. Nos. 7,964,204, 8,410,153, US 2011/0152312, US 2010/0254960A1, US2011/0159107, US2012/0309620, US2012/0030841, US2010/0069247, WO2007/125984, WO 2012/086462, U.S. Pat. No. 8,318,757, US 2011/0144349,U.S. Pat. No. 8,053,452; US 2010/0137612, US 2010/0254959, US2011/152081, WO 2012/089623, WO 2012/089622, U.S. Pat. Nos. 8,119,671;7,947,715; WO 2102/120135, WO 2012/107533, WO 2011/157748, US2011/0245274, US 2011/0245239, US 2012/0232026, US 2012/0077765, US2012/0035122, US 2011/0251247, WO 2011/154433, WO 2011/154434, US2012/0238517, US 2011/0166193, WO 2011/104088, WO 2011/104087, WO2011/104089, US 2012/015946, US 2009/0143410, WO 2007/123855 A2, US2011/0118212, U.S. Pat. No. 7,951,828 & U.S. Pat. No. 7,662,972, US2010/0137372 A1, US 2010/0179194 A2, US 2011/0086886 A2, US 2011/0059988A1, US 2010/0179195 A1, U.S. Pat. Nos. 7,897,630, 7,951,828 and7,662,972, all of which are incorporated herein by reference in theirentirety.

In another embodiment of the invention, nodulisporic acid and itsderivatives (a class of known acaricidal, anthelmintic, anti-parasiticand insecticidal agents) may be combined with compound I or compound II.These compounds are used to treat or prevent infections in humans andanimals and are described, for example, in U.S. Pat. Nos. 5,399,582,5,962,499, 6,221,894 and 6,399,786, all of which are hereby incorporatedby reference in their entirety.

In another embodiment, anthelmintic compounds of the amino acetonitrileclass (AAD) of compounds such as monepantel (Zolvix), and the like, maybe combined with compound I or compound II. These compounds aredescribed, for example, in WO 2004/024704 and U.S. Pat. No. 7,084,280(incorporated by reference); Sager et al., Veterinary Parasitology,2009, 159, 49-54; Kaminsky et al., Nature vol. 452, 13 Mar. 2008,176-181.

The compounds of the invention may also be combined with anotheraryloazol-2-yl cyanoethylamino compounds such as those described in U.S.Pat. No. 8,088,801 to Soll et al., which is incorporated herein byreference, and thioamide derivatives of these compounds, as described inU.S. Pat. No. 7,964,621, also incorporated herein by reference.

Compound I or compound II may also be combined with paraherquamidecompounds and derivatives of these compounds, including derquantel (seeOstlind et al., Research in Veterinary Science, 1990, 48, 260-61; andOstlind et al., Medical and Veterinary Entomology, 1997, 11, 407-408).The paraherquamide family of compounds is a known class of compoundsthat include a spirodioxepino indole core with activity against certainparasites (see Tet. Lett. 1981, 22, 135; J. Antibiotics 1990, 43, 1380,and J. Antibiotics 1991, 44, 492). In addition, the structurally relatedmarcfortine family of compounds, such as marcfortines A-C, are alsoknown and may be combined with the formulations of the invention (see J.Chem. Soc.—Chem. Comm. 1980, 601 and Tet. Lett. 1981, 22, 1977). Furtherreferences to the paraherquamide derivatives can be found, for example,in WO 91/09961, WO 92/22555, WO 97/03988, WO 01/076370, WO 09/004432,U.S. Pat. Nos. 5,703,078 and 5,750,695, all of which are herebyincorporated by reference in their entirety.

In another embodiment of the invention, compound I or compound II may becombined with a spinosyn active agent produced by the soil actinomyceteSaccharopolyspora spinosa (see, for example Salgado V. L. and Sparks T.C., “The Spinosyns: Chemistry, Biochemistry, Mode of Action, andResistance,” in Comprehensive Molecular Insect Science, vol. 6, pp.137-173, 2005) or a semi-synthetic spinosoid active agent. The spinosynsare typically referred to as factors or components A, B, C, D, E, F, G,H, J, K, L, M, N, O, P, Q, R, S, T, U, V, W, or Y, and any of thesecomponents, or a combination thereof, may be used in the compositions ofthe invention. The spinosyn compound may be a 5,6,5-tricylic ringsystem, fused to a 12-membered macro cyclic lactone, a neutral sugar(rhamnose), and an amino sugar (forosamine). These and other naturalspinosyn compounds, including 21-butenyl spinosyn produced bySaccharopolyspora pagona, which may be used in the compositions of theinvention, may be produced via fermentation by conventional techniquesknown in the art. Other spinosyn compounds that may be used in thecompositions of the invention are disclosed in U.S. Pat. Nos. 5,496,931;5,670,364; 5,591,606; 5,571,901; 5,202,242; 5,767,253; 5,840,861;5,670,486; 5,631,155 and 6,001,981, all incorporated by reference hereinin their entirety. The spinosyn compounds may include, but are notlimited to, spinosyn A, spinosyn D, spinosad, spinetoram, orcombinations thereof. Spinosad is a combination of spinosyn A andspinosyn D, and spinetoram is a combination of 3′-ethoxy-5,6-dihydrospinosyn J and 3′-ethoxy spinosyn L.

In general, the additional active agent is included in the compositionin an amount of between about 0.1 μg and about 1000 mg. More typically,the additional active agent may be included in an amount of about 10 μgto about 500 mg, about 1 mg to about 300 mg, about 10 mg to about 200 mgor about 10 mg to about 100 mg.

In other embodiments of the invention, the additional active agent maybe included in the composition to deliver a dose of about 5 μg/kg toabout 50 mg/kg per weight of the animal. In other embodiments, theadditional active agent may be present in an amount sufficient todeliver a dose of about 0.01 mg/kg to about 30 mg/kg, about 0.1 mg/kg toabout 20 mg/kg, or about 0.1 mg/kg to about 10 mg/kg of weight ofanimal. In other embodiments, the additional active agent may be presentin a dose of about 5 μg/kg to about 200 μg/kg or about 0.1 mg/kg toabout 1 mg/kg of weight of animal. In still another embodiment of theinvention, the additional active agent is included in a dose betweenabout 0.5 mg/kg to about 50 mg/kg.

Example 1: Preparation of Compound 2, 2-bromo-4,5-dichlorotoluene

3,4-Dichlorotoluene (100 g, 1 equivalent (eq.)) and iron tribromide(55.1 g) were added to 500 mL dichloromethane and cooled to about −5° C.Bromine (99.2 g) was diluted in 100 mL (1 volume (vol.)) dichloromethaneand added dropwise to the mixture and the resulting mixture was stirredat about −5° C. The reaction mixture was treated with 12.5% aqueousNaHSO₃ (500 mL) at 20° C. and stirred for 30 min. The two phases wereallowed to separate and the separated organic layer was washed withsaturated aqueous NaHCO₃(600 mL, 6 vol.), brine (500 mL, 5 vol.), andthen concentrated under vacuum to about 4-5 vol. Methanol was added todouble the volume and the resulting solid filtered, washed withmethanol, and dried, to provide 120 g of compound 2 in a purity of99.7%.

Example 2: Preparation of Compound 3, 2-formyl-3,4-dichlorotoluene

N-Butyllithium (31.2 mL, 2.4 M, 2.0 eq.) was added to anhydroustetrahydrofuran (20 mL) at about −40 to −50° C. under nitrogen gas. Theresulting solution was cooled to about −70° C. Compound 2 was (10 g, 1eq.) added dropwise as a solution in anhydrous tetrahydrofuran (20 mL)and stirred for 2 hours at about −70° C. to about −80° C.N,N-dimethylformamide (9.1 g, 3 eq) was added and the temperatureallowed to warm to about 10° C. Afterwards, aqueous hydrochloric acid(64 mL, 2.6 M) was added and isopropyl acetate (30 mL) added. Theorganic layer was separated, washed twice with brine (50 mL) and thevolume reduced under vacuum at ≤about 40° C. N-heptane was added totriple the volume and then concentrated under vacuum, and then repeated3 times until the content of THF and isopropyl acetate was determined tobe less than 3% by weight. The mixture was stirred for 2 hours at about−5° C. to 0° C., the resulting precipitate filtered and washed withn-Heptane. Compound 3 (6.1 g, 99.7% purity) was obtained as an off-whitesolid.

Example 3: Preparation of Compound 4,3,4-dichloro-5-formyl-2-nitrotoluene

Compound 3 (37.8 g, 1 eq.) was added to concentrated sulfuric acid (189mL, 5 vol.) in portions at −5° C. to 0° C. Fuming nitric acid (25 mL,2.8 eq.) was added dropwise to the reaction mixture over 15 min and thereaction maintained at −5° C. to 0° C. for 3 hours. Ice water (1 L) wasadded and the resulting mixture stirred for 2 hours and allowed to riseto ambient temperature. The resulting solid was collected and rinsedwith water (12 ml, 3 vol.) twice. The resulting filter cake was treatedwith saturated aqueous NaHCO₃ solution (120 mL) and the resulting solidwas filtered to provide 43 g of crude Compound 4 (92.7% purity).

Example 4: Preparation of Compound 5,3,4-dichloro-5-difluoromethyl-2-nitrotoluene

Compound 4 (100 g, 1 eq.) was added to a liter (10 vol.) ofdichloromethane and the resulting solution cooled to about 0° C.Bis(2-methoxyethyl)aminosulfurtrifluoride (“BAST”, 113.4 g, 1.2 eq.) wasadded dropwise to the mixture and stirred at about 0° C. Water (400 mL)was added at about 5° C., and the mixture adjusted to pH 7-8 using 15%Na₂CO₃ solution (about 600 mL). The organic phase was separated andwashed with brine (500 mL), concentrated under vacuum to about 3 vol.The resulting residue was mixed with n-heptane (3 vol.) and againconcentrated under vacuum. The mixture was stirred for 2 hours at about0° C. and the solid collected by filtration. The resulting filter cakewas washed with n-heptane (100 mL×2) and dried to provide Compound 5 (86g, 90.1% purity) as a light yellow solid.

Example 5: Preparation of Compound 6,2,3-dichloro-5-difluoromethyl-6-methylaniline

Compound 5 (50 g, 1 eq.) was added to methanol (250 mL, 5 vol.) andpalladium on carbon (5 g, 50% in water, 0.10 w/w) added. The reactionmixture was subjected to hydrogen gas at 10 atm at 40-45° C. Thereaction was depressurized and the mixture filtered through diatomaceousearth and the filtrate concentrated at 40±5° C. to about 2-3 volumes.Ethyl acetate (3 vol.) was added to the mixture and the resultingmixture concentrated under vacuum at less than 45° C. to about 2-3volumes. N-heptane (3 vol.) was added to the resulting residue and thenthe mixture was concentrated under vacuum at less than 45° C. to about2-3 vol. The n-heptane mixture was stirred for 2 h at about −5 to 0° C.,and the resulting precipitate collected, washed with heptane (2×50 mL)to provide Compound 6 (35.6 g, 95.5% purity) as a yellow solid.

Example 6: Preparation of Compound 7a

Glacial acetic acid (3.1 L, 8 vol.) and Compound 6 (385 g, 1 eq.) weremixed and stirred for 30 min, and the resulting mixture cooled to about0°−10° C. A solution of sodium nitrite (130 g, 1.1 eq.) in 65 mL ofwater was added in portions in order to maintain the temperature atabout 0°-10° C. The mixture was poured into 20 L of ice water inportions to maintain the temperature at about 0°−15° C. The resultingprecipitate was collected, washed with water (2 L), heptane (1.2 L) anddried under vacuum to provide a crude product. The crude product wasslurried in heptane, re-filtered, and dried, to obtain Compound 7a, (327g, 95.8% purity).

Example 7: Preparation of Compound 7b

Compound 7a (800 g, 1 eq.) was added to dichloromethane (32 L). SodiumCarbonate (716 g, 2 eq.) in water (8 L) was added, followed bytetrabutylammonium bromide (217 g). The mixture was cooled to 0-5° C.,and chloroacetone (375 g, 1.2 eq.) was added. The mixture was warmed to15-20° C. and stirred 24 hours. The organic layer was separated, washedwith water (4 L, 5 vol.) and brine (4 L), and concentrated under vacuumat less than 40° C. The resulting liquid was heated to 35-40° C. andstirred for one hour, then cooled to 0-5° C. and stirred for 2 hours.The resulting precipitate was collected and washed with a 1:1 v/vmixture of dichloromethane: n-heptane (1.6 L total) and dried to obtainCompound 7b as a brown solid (497 g, 97.9% purity).

Example 8: Preparation of Compound 8

Compound 7b (2.0 kg, 1 eq.) was mixed with N,N-dimethylformamide (10 L,5 vol.), and ammonium chloride (730 g, 2 eq.) added to the mixture.Ammonium hydroxide (4.88 L, 7 M, 5 eq.) was added, and the resultingmixture cooled to 10-15° C. Trimethylsilyl cyanide (1.36 kg, 2 eq.) wasadded while maintaining the temperature at about 10-15° C. The reactionwas heated to 40-45° C. for 24 hours, then diluted into water (40 L, 20vol.), and the resulting mixture stirred for 2 hours. The resultingprecipitate was collected and washed with water (3×2 L), and dried at50-55° C. for 16 hours to provide Compound 8 as a light yellow solid(2.05 kg, 97.4% purity).

Example 9: Preparation of Compound I

Compound 8 (3.5 kg, 1 eq.) was added to tetrahydrofuran (35 L, 10 vol.)and cooled to 0-5° C. Triethylamine (1.67 kg, 1.5 eq.) was added,followed by 4-(trifluoromethylthio)benzoyl chloride (2.80 kg, 1.05 eq.)while maintaining the temperature at 0-5° C. The reaction mixture wasstirred for 2 hours, and concentrated at 40° C. to 2-3 volumes.Dichloromethane (17.5 L, 5 vol.) was added and the mixture concentratedunder vacuum at about 40° C. or less to 2-3 volumes. Dichloromethane(52.5 L) was added and the organic phase washed with aqueoushydrochloric acid (17.5 L, 0.5 M), saturated aqueous NaHCO₃ solution(17.5 L), water (17.5 L) and brine (17.5 L). The organic phase wasconcentrated at 40° C. to about 2-3 volumes, then cooled to 0-5° C. andstirred for 2 hours. The resulting precipitate was collected and thefiltrate washed with dichloromethane (3×3.5 L). The crude product (4.66kg) was added to dichloromethane (7 L, 2 vol.), the mixture heated to40° C., and stirred for 2 hours. The mixture was cooled to 0-5° C. andstirred for 2 hours. The resulting solid was collected and washed withdichloromethane (7 L) and dried to obtain compound I as a light brownsolid (4.15 kg, 99.7% purity, 72.3% yield). Purification of Compound Ito 99.9% purity was obtained by recrystallization in methanol.

Example 10: Three Compounds from Patent Publication No. WO2010/056999(999 App)

Compound I, and Compound II were tested in vitro against Haemonchuscontortus larvae to determine the minimum concentration at which thecompounds inhibited the motility of the larvae by 90% (MIC₉₀). Thefollowing procedure was used for the study: Twenty L1 Haemonchuscontortus larvae were added to wells of a microtitre plate containing anutrient medium and the test compound in DMSO. The microtitre plate washeld at 27° C. and 97% Relative humidity for a 4 day period. Under theseconditions the added larvae develop to the L3 stage. The efficacy of acompound is determined based on the motility of the resulting L3 larvaeand compared to the motility of control wells treated with DMSO only.

The MIC₉₀ of each compound is shown below in Table 1:

TABLE 1 Compound MIC₉₀ (ppm) I 0.0003 ‘999 App, 2.038 0.0024 ‘999 App,2.041 0.0024 ‘999 App, 2.049 0.0012 II 0.0012

Compound 2.038 is

Compound 2.041 is

Compound 2.049 is

Example 11: In Vivo Efficacy of Compound I Alone and in Combination withan Avermectin

The efficacy of Compound I against parasitic gastrointestinal nematodesin cattle when administered orally as an oral solution was studied.Thirty male castrate dairy calves of approximately 8 to 12 weeks of agewere experimentally infected with parasitic nematodes. The calves wereinoculated with Haemonchus placei and Ostertagia ostertagi on Day −33and with Cooperia punctata and Cooperia oncophora on Day −21. Calveswere allocated to one of the six treatment groups. Calves in TreatmentGroup 1 were not treated. Calves in Treatment Groups 2-6 were treated onDay 0 as outlined in the Table 2 below with a formulation containing 5%(w/v) of Compound I in a carrier comprising 50% (v/v) PEG 400 with theremainder (QS to 130 mL0 PEG 300.

TABLE 2 Treatment Group Active Agent Dose 1 Not treated NA 2 Compound I2 mg/kg 3 eprinomectin 0.075 mg/kg 4 ivermectin 0.150 mg/kg 5 CompoundI + 2 mg/kg + eprinomectin 0.075 mg/kg 6 Compound I + 2 mg/kg +ivermectin 0.150 mg/kg

All calves were euthanized on Day 16 and the abomasum and smallintestine were recovered from each calf and processed for parasiterecovery. All five calves in the untreated control group harboredadequate infections of H. placei, O. ostertagi, C. punctate and C.oncophora. The efficacy of each treatment group relative to the controlgroup is shown in Table 3 below:

% Reduction in Worm Counts Treatment H. placei O. ostertagi O. ostertagiC. punctata C. oncophora Cooperia Group Adults Males Females Males Malesspp. Females Group 2 100.0 96.3 96.4 100.0 83.0 90.9 Group 3 98.9 95.799.4 94.7 0 55.8 Group 4 82 75 81 91 0 46 Group 5 100 96.3 99.2 99.987.9 90.9 Group 6 100.0 98.9 98.6 99.9 98.7 90.4

As shown in Table 3, Compound I was significantly more effective againstC. oncophora males and Cooperia spp. female worms compared witheprinomectin (Group 3) or ivermectin (Group 4). In addition, althoughivermectin alone was not effective against C. oncophora male worms, thecombination of Compound I and ivermectin provided almost 100% efficacy.These results demonstrate the surprising efficacy of Compound I againstgastrointestinal nematodes, including those that are less susceptible totreatment with avermectins. The efficacy demonstrated by Compound Iagainst nematode strains that are not susceptible to macrocyclic lactonetherapy is surprising and unexpected. In addition, the efficacydemonstrated by a combination of Compound I and a macrocyclic lactoneagainst these nematodes is also surprising and unexpected.

We claim:
 1. A compound of formula I:

and/or an acceptable salt thereof and/or an enantiomer thereof.
 2. Thecompound of claim 1, wherein the compound is enriched in an enantiomer.3. The compound of claim 2, wherein the compound is enriched in the(R)-enantiomer.
 4. The compound of claim 2, wherein the compound isenriched in the (R)-enantiomer in a ratio of at least 95:5 by weight. 5.A parasiticidal composition comprising the compound formula I of claim1, or salt thereof, and a pharmaceutically acceptable carrier.
 6. Thecomposition of claim 5, wherein the composition is formulated for oraladministration, topical administration or injectable administration. 7.The composition of claim 5 further comprising one or more additionalparasiticidal active agents.
 8. The composition of claim 7, wherein theadditional parasiticidal active agent is selected from the groupconsisting of one or more macrocyclic lactones, one or more spinosyncompounds, one or more spinosoid compounds, one or more cyclicdepsipeptides, one or more benzimidazoles, levamisole, pyrantel,morantel, praziquantel, closantel, clorsulon, one or more aminoacetonitrile active agents, one or more insect growth regulators, one ormore pyrethoids, one or more phenylpyrazoles, one or more neonicotinoidsand one or more different aryloazol-2-yl cyanoethylamino active agents,or a combination thereof.
 9. The composition of claim 8, wherein theadditional active agent(s) is a macrocyclic lactone.
 10. The compositionof claim 9, wherein the macrocyclic lactone is an avermectin ormilbemycin selected from the group consisting of abamectin, dimadectin,doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin,selamectin, milbemectin, milbemycin D, milbemycin A₃, milbemycin A₄,milbemycin oxime, moxidectin and nemadectin.
 11. The composition ofclaim 10, wherein the macrocyclic lactone is ivermectin, eprinomectin,selamectin, milbemycin oxime or moxidectin.
 12. The composition of claim6, wherein the composition is a chewable composition.
 13. Thecomposition of claim 6, wherein the composition is an oral drenchcomposition.
 14. The composition of claim 6, wherein the composition isa pour-on composition.
 15. The composition of claim 6, wherein thecomposition is a spot-on composition.
 16. A method for treating anendoparasitic infection in a mammal which comprises administering aneffective amount of the compound of formula I in claim 1, or theparasiticidal composition of claim 5, to the animal.
 17. The method ofclaim 16, wherein the endoparasiticidal infection is caused by anendoparasite selected from the group consisting of Anaplocephaela(Anoplocephala), Ancylostoma, Anecator, Ascaris, Brugia, Bunostomum,Capillaria, Chabertia, Cooperia, Cyathostomum, Cylicocyclus,Cylicodontophorus, Cylicostephanus, Craterostomum, Dictyocaulus,Dipetalonema, Dipylidium, Dirofilaria, Dracunculus, Echinococcus,Enterobius, Fasciola, Filaroides, Habronema, Haemonchus, Metastrongylus,Moniezia, Necator, Nematodirus, Nippostrongylus, Oesophagostumum,Onchocerca, Ostertagia, Oxyuris, Paracaris, Schistosoma, Strongylus,Taenia, Toxocara, Strongyloides, Toxascaris, Trichinella, Trichuris,Trichostrongylus, Triodontophorous, Uncinaria, Wuchereria, andcombinations thereof.
 18. The method of claim 17, wherein theendoparasite is Haemonchus contortus, Ostertagia circumcincta,Trichostrongylus axei, Trichostrongylus colubriformis, Cooperiacurticei, Nematodirus battus or combinations thereof.
 19. The method ofclaim 16, wherein the endoparasite is resistant to avermectin ormilbemycin therapy.